Preclinical and Early Clinical Development of PTC596, a Novel Small-Molecule Tubulin-Binding Agent

Jernigan, Finith E.; Branstrom, Arthur; Baird, John D.; Cao, Liangxian; Dali, Mandar; Furia, Bansri; Kim, Min Jung; O’Keefe, Kylie; Kong, Ronald; Laskin, Oscar L.; Colacino, Joseph M.; Pykett, Mark; Mollin, Anna; Sheedy, Josephine; Dumble, Melissa; Moon, Young-Choon; Sheridan, Richard Brinsley; Mühlethaler, Tobias; Spiegel, Robert J.; Prota, A.E.; Steinmetz, Michel O.; Weetall, Marla

doi:10.1158/1535-7163.mct-20-0774

Cited by 16 publications

(17 citation statements)

References 41 publications

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“…To confirm further the effect of DHODH inhibition in vivo , a second study was performed with the structurally related DHODH inhibitor, PTC-868 ( 37 ). As shown in Supplementary Figure 5A , PTC-868 reduced the rate of MOLM-13 tumor growth.…”

Section: Resultsmentioning

confidence: 99%

Emvododstat, a Potent Dihydroorotate Dehydrogenase Inhibitor, Is Effective in Preclinical Models of Acute Myeloid Leukemia

et al. 2022

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Blocking the pyrimidine nucleotide de novo synthesis pathway by inhibiting dihydroorotate dehydrogenase (DHODH) results in the cell cycle arrest and/or differentiation of rapidly proliferating cells including activated lymphocytes, cancer cells, or virally infected cells. Emvododstat (PTC299) is an orally bioavailable small molecule that inhibits DHODH. We evaluated the potential for emvododstat to inhibit the progression of acute myeloid leukemia (AML) using several in vitro and in vivo models of the disease. Broad potent activity was demonstrated against multiple AML cell lines, AML blasts cultured ex vivo from patient blood samples, and AML tumor models including patient-derived xenograft models. Emvododstat induced differentiation, cytotoxicity, or both in primary AML patient blasts cultured ex vivo with 8 of 10 samples showing sensitivity. AML cells with diverse driver mutations were sensitive, suggesting the potential of emvododstat for broad therapeutic application. AML cell lines that are not sensitive to emvododstat are likely to be more reliant on the salvage pathway than on de novo synthesis of pyrimidine nucleotides. Pharmacokinetic experiments in rhesus monkeys demonstrated that emvododstat levels rose rapidly after oral administration, peaking about 2 hours post-dosing. This was associated with an increase in the levels of dihydroorotate (DHO), the substrate for DHODH, within 2 hours of dosing indicating that DHODH inhibition is rapid. DHO levels declined as drug levels declined, consistent with the reversibility of DHODH inhibition by emvododstat. These preclinical findings provide a rationale for clinical evaluation of emvododstat in an ongoing Phase 1 study of patients with relapsed/refractory acute leukemias.

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Section: Resultsmentioning

confidence: 99%

Emvododstat, a Potent Dihydroorotate Dehydrogenase Inhibitor, Is Effective in Preclinical Models of Acute Myeloid Leukemia

et al. 2022

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“…The drug has also been explored for treatment of other cancers, for example, mantle cell lymphoma [ 182 ], cancer stem-like cells [ 99 ], multiple myeloma [ 183 ], and glioblastoma multiforme [ 184 ]. PTC-596 has been used in clinical phase 1 for conditions including diffuse intrinsic pontine glioma and leiomyosarcoma [ 185 , 186 ]. Moreover, a novel inhibitor, RU-A1, was developed based on the RNA three-dimensional (3D) structure of Bmi-1 and showed stronger potency than PTC-209 in targeting CSCs [ 187 ].…”

Section: Clinical Characteristics and Cancer Therapy Of Bmi-1mentioning

confidence: 99%

The Crucial Roles of Bmi-1 in Cancer: Implications in Pathogenesis, Metastasis, Drug Resistance, and Targeted Therapies

Shi

et al. 2022

IJMS

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B-cell-specific Moloney murine leukemia virus integration region 1 (Bmi-1, also known as RNF51 or PCGF4) is one of the important members of the PcG gene family, and is involved in regulating cell proliferation, differentiation and senescence, and maintaining the self-renewal of stem cells. Many studies in recent years have emphasized the role of Bmi-1 in the occurrence and development of tumors. In fact, Bmi-1 has multiple functions in cancer biology and is closely related to many classical molecules, including Akt, c-MYC, Pten, etc. This review summarizes the regulatory mechanisms of Bmi-1 in multiple pathways, and the interaction of Bmi-1 with noncoding RNAs. In particular, we focus on the pathological processes of Bmi-1 in cancer, and explore the clinical relevance of Bmi-1 in cancer biomarkers and prognosis, as well as its implications for chemoresistance and radioresistance. In conclusion, we summarize the role of Bmi-1 in tumor progression, reveal the pathophysiological process and molecular mechanism of Bmi-1 in tumors, and provide useful information for tumor diagnosis, treatment, and prognosis.

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“…BMI1 hyperphosphorylation by the small molecule PTC596 impairs protein function [ 151 ]. Recent Phase I results indicate that orally bioavailable PTC596 has a tolerable human safety profile and is pre-clinically efficacious in mice as a monotherapy against leiomyosarcomas and glioblastoma, supporting its further development [ 152 ]. This is exciting, considering that clinical trials targeting the polycomb complex have to date focused solely on EZH2, the catalytic domain of polycomb repressive complex 2.…”

Section: Role Of the Epigenome In Therapeutic Resistancementioning

confidence: 99%

Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies

Rubanov

Berico

Hernando

2022

Cancers

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Melanoma is an aggressive skin cancer reliant on early detection for high likelihood of successful treatment. Solar UV exposure transforms melanocytes into highly mutated tumor cells that metastasize to the liver, lungs, and brain. Even upon resection of the primary tumor, almost thirty percent of patients succumb to melanoma within twenty years. Identification of key melanoma genetic drivers led to the development of pharmacological BRAFV600E and MEK inhibitors, significantly improving metastatic patient outcomes over traditional cytotoxic chemotherapy or pioneering IFN-α and IL-2 immune therapies. Checkpoint blockade inhibitors releasing the immunosuppressive effects of CTLA-4 or PD-1 proved to be even more effective and are the standard first-line treatment. Despite these major improvements, durable responses to immunotherapy and targeted therapy have been hindered by intrinsic or acquired resistance. In addition to gained or selected genetic alterations, cellular plasticity conferred by epigenetic reprogramming is emerging as a driver of therapy resistance. Epigenetic regulation of chromatin accessibility drives gene expression and establishes distinct transcriptional cell states. Here we review how aberrant chromatin, transcriptional, and epigenetic regulation contribute to therapy resistance and discuss how targeting these programs sensitizes melanoma cells to immune and targeted therapies.

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Preclinical and Early Clinical Development of PTC596, a Novel Small-Molecule Tubulin-Binding Agent

Cited by 16 publications

References 41 publications

Emvododstat, a Potent Dihydroorotate Dehydrogenase Inhibitor, Is Effective in Preclinical Models of Acute Myeloid Leukemia

Emvododstat, a Potent Dihydroorotate Dehydrogenase Inhibitor, Is Effective in Preclinical Models of Acute Myeloid Leukemia

The Crucial Roles of Bmi-1 in Cancer: Implications in Pathogenesis, Metastasis, Drug Resistance, and Targeted Therapies

Epigenetic Mechanisms Underlying Melanoma Resistance to Immune and Targeted Therapies

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